Cyclitols are cycloalkanes containing one hydroxyl group on each of three or more ring carbons. The most abundant members of the cyclitol genus are the inositols (1,2,3,4,5,6-hexahydroxy-cyclohexanes), the most important stereoisomer of this family being myo-inositol (I). Myo-inositol has hydroxyl groups in the 1-, 2-, 3-, and 5- positions of the cycloaliphatic ring that lie in one side of a stereochemical plane, and two hydroxyl groups in the 4- and 6-positions that lie on the other. Phosphorylated derivatives of cyclitols and inositols, wherein one or more hydroxyl groups are converted to phosphate monoesters, are generally referred to, respectively, as cyclitol phosphates or inositol phosphates.
The biological function of cyclitols, in particular inositols, depends on both the extent of phosphorylation of the hydroxyl groups, as well as the position and stereochemistry of the resulting phosphate functionalities. Complex proteins called kinases catalyze reactions that put phosphate groups on specific sites of a substrate. Cellular processes in mammals, including man, depend, at least in part, on inositol phosphates. Certain inositol phosphates function as “second messengers”, that is, molecules that provide the means by which neurotransmitters, growth factors or hormones alter processes inside cells without necessarily penetrating the cells they affect. D-myo-inositol-1-phosphate is an important second messenger in cellular signal transduction pathways. Increased concentrations of these second messengers, in turn, activate certain enzymatic processes within the cells. Similarly, some growth factors such as platelet derived growth factor (PDGF) cause an increased production of inositol phosphates in the cells they affect. Intracellular concentrations of inositol phosphates also appear to play a role in the regulation of cell division and the inflammatory response. Because of the potential medicinal importance of the natural inositol phosphates, including its analogs, derivatives and isomers, there has been considerable interest in these compounds, which is reviewed in the art (Science, 234: 1519 (1986); Scientific American, 253: 142 (1985)).
Studies pertaining to medicinal application of inositol phosphates have, however, been limited both by low yields of isolable material from natural sources, and the tedious processes involved in their isolation and purification. This is mainly attributed to the fact that the inositol substrate offers not only multiple reactive sites, but also the possibility of enantiomeric products for each derivatized reactive site. Synthetic methods for preparing a desired enantiomer, therefore, usually involves either elaborate protecting-group strategies including use of chiral auxiliaries, or neccessitates laborious isolation, such as for example, by selective recrystallization or enzymatic resolution. Practical and efficient synthetic methods for selectively preparing significant larger amounts in high purity of specific enantiomers of phophorylated inositols and their analogs remain a largely unsolved issue. It is, therefore, desirable to develop efficient synthetic methods for providing adequate quantities of enantiomerically pure synthetic insitol phosphates for applications involving their medicinal use.